Caffeine is a naturally occurring methylxanthine (1,3,7-trimethylxanthine) derived from several plants, including coffee, cocoa and cola. It is classified as a mild central nervous system stimulant. It is commonly used to combat fatigue and has some benefit in the treatment of migraine headaches. By itself it has little or no analgesic efficacy, but caffeine will enhance the action of analgesic drugs by 10–40%, particularly acetaminophen and opioids.
The methylxanthines exhibit complex mechanistic and pharmacological pathways affecting a variety of signaling pathways. With regard to nociception, the two most important mechanisms of action are their ability to block receptor-mediated actions of adenosine and their ability to inhibit cyclic nucleotide phosphodiesterase enzymes.
Adenosine is a nearly ubiquitous inhibitory neuromodulator. Importantly, it plays a key role in the production of sleep. Therefore, the blockade of adenosine receptors by methylxanthines will cause alertness. Research has shown that adenosine modulates the release of the neurotransmitter, norepinephrine. Norepinephrine is an important neurotransmitter in the descending inhibitory circuitry activated by dihydromorphine and other mu opioid receptor agonists. Therefore it follows that the blockade of adenosine receptors by methylxanthines also modulates the activity of opioid analgesics.
With regard to the inhibition of phosphodiesterase enzymes, which catalyzes the breakdown of cyclic AMP to 5′-AMP and cyclic GMP to 5′-GMP, the presence of methylxanthines will cause accumulation of the two cyclic nucleotides, resulting in an increase in the signal transduction mediated by these pathways. Thus, caffeine modulates the signaling initiated by many of the G-protein coupled receptors, including opioid receptors.
Compositions containing NSAIDs (non-steroidal anti-inflammatory drugs) in combination with varying amounts of caffeine have been marketed in the past. Examples include combinations containing aspirin, acetaminophen, and/or phenacetin. Narcotic analgesics have also been added to the aspirin/acetaminophen/phenacetin/caffeine combinations. The rational for using such combinations is to reduce the dose of each analgesic, and thus reduce adverse effects and toxicity, while retaining or increasing analgesic efficacy.
For many types of pain (e.g. common headache, osteoarthritis) acetaminophen has equal potency and efficacy to acetylsalicylic acid (aspirin). However, the safety of acetaminophen has been questioned. There are approximately 100,000 cases of acetaminophen overdose annually, with approximately 30 deaths resulting. (Clissold, 1980; McGoldrick et al. 1997). Acetaminophen has a toxic metabolite, N-acetyl-benzoquinoneimine (NAPQI), which depletes hepatic and renal glutathione, a cytoprotective endogenous metabolite (Mason & Fischer, 1986; Mitchell et al., 1983). Hepatic and renal toxicity with acetaminophen can occur at doses only 4- to 8-fold higher than the maximum recommended analgesic dose (Neuberger et al., 1980). Pharmaceutical combinations that contain acetaminophen and a centrally acting analgesic may be even more dangerous than acetaminophen alone. With repeated use these combinations require higher doses to produce the same analgesic effect because of an increase in tolerance. As the dose of the combination is increased to compensate for analgesic tolerance, the safety of the drug decreases as the higher doses of the acetaminophen component increase hepatic and renal toxicity.
In U.S. Pat. No. 5,554,636 (Bazan et al.) and U.S. Pat. No. 5,621,110 (Bazan et al.), two of the inventors herein disclosed the series of N-acylated 4-hydroxyphenylamine derivatives linked via an alkylene bridge to the nitrogen atom of a 1,2-benzisothiazol-3(2H)-one 1,1-dioxide group along with the process for their preparation and methods of their use for alleviating pain. The disclosures of these patents are incorporated herein by reference. The SCP series is structurally depicted by the following general formula:
wherein n is a number from 1 to 5. These new non-narcotic analgesics surprisingly possess high analgesic activity free from antipyretic activity, do not suppress blood coagulation, and display little hepatotoxic effect. When the term “SCP series” is used herein, it is understood that any of the pharmaceutically suitable salts thereof are included by the term.
The analgesic profiles of the SCP series are at least as good as that of acetaminophen. As expected, both types of drugs show little or no activity in the tail-flick and hotplate tests when compared with codeine. SCP-1 is more potent in the abdominal stretch, formalin, and Freund's adjuvant-induced inflammation assays of analgesia than acetaminophen. Acetaminophen is a potent antipyretic, whereas SCP-1 at doses up to 904 μmoles/kg (300 mg/kg) has no antipyretic effect. SCP-1 is lower in toxicity, and, of even greater importance, lower in hepatotoxicity (Paul et al., 1998). All of these properties make SCP-1 and related derivatives potentially very useful pharmacologic agents.
These novel non-narcotic analgesics differ substantially in chemical structure from aspirin, acetaminophen and phenacetin and have significantly different biological profiles, thus the SCP series of analgesics can be formulated into novel pharmaceutical combinations with caffeine to elicit enhanced analgesia without antipyretic activity and little hepatotoxic effect.